YC 1 br H R agonists In search for potent

H2R agonists In search for potent and selective H2R agonists, comprehensive structure–activity relationship studies have been conducted and led to the first H2R agonists, e.g. 4(5)-methylhistamine (16) which is actually now used as selective H4R agonist (Fig. 4) (Durant et al., 1975, Lim et al., 2005). Other small molecule ligands used as H2R agonists are the aminothiazole derivative amthamine (17) in which imidazole was replaced by a basic thiazole derivative (Eriks et al., 1993, Weinstein et al., 1976) and the isothiourea YC 1 dimaprit (18) which shows moderate affinity and selectivity for H2Rs (Garbarg et al., 1992). Interestingly, an increased affinity, which is higher than that of histamine was found with impromidine (19) although such ligands concurrently demonstrate some H3R antagonist activities. Noticeably, the homohistamine elements with the guanidine structure on impromidine (19) and (R)-(-)-sopromidine (20) are mainly responsible for receptor activation whereas the other elements are predominantly considered as affinity increasing moieties (Dove et al., 2004). In this respect, the chiral forms of sopromidine are sometimes used as helpful pharmacological tools as the (R)-(-) enantiomer sopromidine (20) is a potent H2R agonist, whereas the (S)-(+)-isoform displays moderate antagonist properties in some assays. In the latter two compounds, namely impromidine (19) and (R)-(-)-sopromidine (20), the amine group of histamine has been replaced by a guanidine functionality which resembles the basicity of amine in being quantitatively protonated under in-vivo conditions to form the cationic form (guanidinium moiety) required for agonistic effect at H2R (Buschauer, 1988, Sterk et al., 1986a, Sterk et al., 1986b). It is worth-fully to denote that H2R agonists are not used therapeutically, despite the fact that impromidine (19) and related imidazolylpropylguanidines were developed as positive inotropic vasodilators for the therapeutic management of severe congestive heart failure. Moreover and due to their physicochemical properties under physiological conditions and the ability to form a guanidinium moiety, e.g. impromidine and (R)-(-)-sopromidine were not suitable for per oral application, as pro-drugs with strong electron withdrawing groups have been applied (Buschauer, 1988). Moreover and aiming at improved drug-like properties, the guanidine group was replaced by an acylguanidine moiety, resulting in substantially reduced basicity (by 4-5 orders of magnitude), but retaining H2R agonistic activity (Ghorai et al., 2008). Unfortunately, many NG-acylated imidazolylpropylguanidines (e.g. UR-AK24, 21) proved to be poorly selective for the H2R as, also, found for impromidine-like ligands. Moreover, it has been found that some N-acylguanidines show an overlapping (partial) agonist profile for H1 and H2R (Xie et al., 2006). However, numerous ligands have high affinity for H3R and H4R and were, therefore, considered as structural leads in the design of novel H3R and H4R ligands. Consequently, the imidazolylpropylguanidine moiety can be seen as a privileged structure for histamine receptor ligands. Also, the selectivity problem was resolved by bioisosteric replacement of the imidazol-4-yl with a 2-aminothiazol-5-yl heterocycle, optionally bearing a 4-methyl substituent as in amthamine. Consequently, 2-Aminothiazoles, e.g. UR-BIT24 (22), are about equipotent to the corresponding imidazoles at the H2R, but devoid of noteworthy activities at H1R, H3R and H4R (Fig. 4) (Kraus et al., 2009).
H2R antagonists The finding that the thiourea derivative, Nα-thioguanylhomohistamine, acts as a partial H2R agonist in a gastric acid secretion test led to the development of the relatively weak H2R antagonist burimamide (23) which was the first selective compound for HR2s (Fig. 4) (Smit et al., 1996a, Smit et al., 1996c, Wyllie et al., 1972a, Wyllie et al., 1972b). Paradoxically, burimamide was later detected as potent histamine H3R antagonist and then also as a histamine H4R agonist (Smit et al., 1996a, Smit et al., 1996c). The robust relationship of ligand binding areas accountable for interaction with receptor can also be comprehended with the first promoted H2R antagonist cimetidine (24) introduced by Sir James Black (Black et al., 1972, Ganellin, 1981), as this ligand with the highly polar cyanoguanidine moiety is analogous to the affinity increasing element in impromidine (Fig. 2). The decreased basicity of a highly polar fundamental group was achieved with the development of ranitidine (nitroethendiamine) (25), famotidine (26) (sulfamoylamidine), or the moderately polar compound zolantidine (aminobenzothiazole, 27) which have reduced penetration into the brain with the exception of zolantidine (Fig. 4) (Baker, 2008, Panula et al., 2015). In the latter ligands, the imidazole moiety of cimetidine has been replaced by other bioisosteric heterocycles to shrink interaction with CYP450:3A4 enzymes and to overcome intellectual property concerns. Whereas the imidazole derivative cimetidine is a potent inhibitor of CYP3A4, the later compounds proved to be applied in much smaller dosage and possess less than 10% of the effects on cytochrom P450 metabolism than cimetidine (Smit et al., 1996a, Smit et al., 1996c). The achievement of such compounds based on comprehensive structure-activity-relationship studies led to much higher safety of the newer H2R antagonists and availability of some of the compounds as OTC drugs. Currently, evidence indicates the involvement of H2Rs in the control of defensive behaviors following activation of the cortical, limbic, and other neural substrates of fear. Thus, zolantidine (27), a lipophilic benzthiazole derivative with a 30-fold higher potency for H2Rs than other peripheral and central HRs, is a potent and CNS penetrant H2R antagonist, and leads to fearful behaviors that can be prevented by prior injection of dimaprit (18), a potent H2R agonist (Fig. 4) (Santos et al., 2002).